Establishing Regulatory Starting Materials & Understanding the ICH

Establishing Regulatory Starting Materials & Understanding the ICH

Blog 2020 01 Establishing Regulatory Starting Materials Understanding ICH

Lessons with James Mencel, Senior Drug Substance Consultant, DSI

There are many ways for companies to get approvals for expedited development. This is primarily based on trials and data from clinical studies. The biggest issue has always been how acceleration impacts CMC. In many cases, the data and the programs need time and cannot be expedited. So how do you ensure CMC doesn't become the bottleneck?

Transitioning chemistry: Regulatory starting materials is the point where change control starts. This is also the point where GMP is introduced into the synthesis of a drug substance. Other changes before that cannot affect API or ultimate drug product.

The ICHQ guidelines: The International Conference on Harmonization compiled the informative ICHQ11. This guideline is a globally agreed framework for facilitating CMC changes efficiently and predictably in drug development.

Companies needing guidance can find a lot more information here on establishing drug substance process controls. Depending on specific circumstances, you may find that the ICHQ11 provides a little flexibility in selecting starting materials. The FDA adopts these guidelines.

Based on ICHQ11, sponsors can develop a process understanding of future changes in synthesis and starting materials methods. It offers clarity on all the data required not just for approval but also for substance quality and patient safety.

Regulators expectations: Understanding regulator expectations ensures that your starting material will have the requisite technical and quality elements to allow for commercialization when you submit NDA and BLA. The information in this application is what you would have accrued over time throughout development.

Begin with the end in mind: Start thinking about controls as early as phase two for consistency and verifiable quality and purity levels. Everything up to the point of the regulatory starting material must be subjected to GMP.

Do you have a perfect understanding of the medication that will be served to patients? This is the question that sums up all regulator concerns, questions, and expectations. Start here and compile all data needed to support your synthetic routes.

Apply Good Manufacturing Practices: GMPs are mandatory from the starting material forward in API. Generally, there is little oversight in starting materials, but regulators expect GMPs to extend further back. With a longer synthetic chain, there are fewer chances of impurities in the final Active pharmaceutical ingredient (API). Minimize switching or choosing new suppliers of starting materials for a consistent level of quality

Gather more data: It takes considerable time to develop a package to support a regulatory starting material proposal. The right package should be backed by extensive data. Detail the process, the points where impurities purge, crystallization points, and other elements that address regulator expectations for staring materials.

Understand FDA vs. EMA on the matter: The FDA is flexible in applying ICH guidelines on a case-by-case basis. In Europe, these are more like rules. It is crucial to figure out how you'd fit this approach. For instance, rules will be different for commercially available materials as intermediate versus those that are available as a commodity.

The big question of impurities: Impurities are the biggest concern that underlies issues raised regarding starting material choice for APIS. Find and clarify the points where the contaminants can be purged. Start with a flow diagram of the material, the molecule, and the process and identify purification points, which could be extractions, crystallization, or chromatography.

Specificity helps: The more detailed you are about these materials purge, the better. If you do spike and fate tests and purge studies at that point and track progress throughout purification, that will strengthen your arguments for LBA and NDA. This downstream control process improves your understanding of what kind of controls you need to have on that proposed material and its quality. Downstream.

Perfect upstream process control: Find out what controls the purity of the proposed starting materials. Impurities can range from metal to rogue solvents like benzene and chloroform. Establish a framework for controlling quality and keeping contaminants below the threshold. You can set specs based on data from purge studies and spike tests. In the end, you'll need to convince FDA or EMA how did this.

Embrace the ICH: The FDA essentially has given you their playbook. The ICH outlines all the things regulators have seen people didn't do that they should have done. Anyone in the drug business cannot afford not to read these guidelines.

Or use the QBD Framework: Quality by design is another useful alternative guideline. You work by a systematic approach to development, beginning with predefined objectives, product and process understanding, and process control.

Here scientists must think about what they need to control in the process going forward to eliminate the problem from the start.

The idea is that when you do a quality by design approach or an enhanced development approach, you want to know as much as you can about your process and where the things that you need to control are.

In a nutshell

Know the process. Apply controls from the onset, and compile data.

Tweetable Quotes

It takes a fair bit of time to develop a package to support a regulatory starting material proposal to an agency. And the better packages are ones that are supported by data…The reason this is important is because the stronger your… Click To TweetI see this as like being an advanced scout watching another team play ball. If you can stand at the field and watch how they approach and do things, you’re prepared when you face that team yourself. And I think if you can approach… Click To TweetOne of the crux issues with choosing a starting material is the whole case you can make about how you purge the impurities from that point forward. Click To TweetI think it’s (the ICH Q11) is a great document. And I think that any process chemist should read it and understand what’s being looked for. Click To TweetWhat it really comes down to is you want to try to understand what’s making your process tick. If you get some new impurity, the process is telling you something. Where is it coming from? Sometimes you get impurities you can’t get… Click To Tweet

Links Mentioned

International Council fo Harmonisation


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Drug Substance

Drug Product


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